Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 162, Issue 6, Pages 1326-1339Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1476-5381.2010.01142.x
Keywords
GABAA ion channels; trans-retrochalcones; allosteric modulators; flavylium salts
Categories
Funding
- ANR [06-0050-01]
- CNRS
- China Scholarship Council
- [18077009]
- [21600019]
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BACKGROUND AND PURPOSE Flavonoids, important plant pigments, have been shown to allosterically modulate brain GABA(A) receptors (GABA(A)Rs). We previously reported that trans-6,4'-dimethoxyretrochalcone (Rc-OMe), a hydrolytic derivative of the corresponding flavylium salt, displayed nanomolar affinity for the benzodiazepine binding site of GABA(A)Rs. Here, we evaluate the functional modulations of Rc-OMe, along with two other synthetic derivatives trans-6-bromo-4'-methoxyretrochalcone (Rc-Br) and 4,3'-dimethoxychalcone (Ch-OMe) on GABA(A)Rs. EXPERIMENTAL APPROACH Whole-cell patch-clamp recordings were made to determine the effects of these derivatives on GABA(A)Rs expressed in HEK-293 cells and in hippocampal CA1 pyramidal and thalamic neurones from rat brain. KEY RESULTS Rc-OMe strongly potentiated GABA-evoked currents at recombinant alpha(1-4)beta(2)gamma(2s) and alpha(4)beta(3)delta receptors but much less at alpha(1)beta(2) and alpha(4)beta(3). Rc-Br and Ch-OMe potentiated GABA-evoked currents at alpha(1)beta(2)gamma(2s). The potentiation by Rc-OMe was only reduced at alpha(1)H101R beta(2)gamma(2s) and alpha(1)beta(2)N265S gamma(2s), mutations known to abolish the potentiation by diazepam and loreclezole respectively. The modulation of Rc-OMe and pentobarbital as well as by Rc-OMe and the neurosteroid 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one was supra-additive. Rc-OMe modulation exhibited no apparent voltage-dependence, but was markedly dependent on GABA concentration. In neurones, Rc-Br slowed the decay of spontaneous inhibitory postsynaptic currents and both Rc-OMe and Rc-Br positively modulated synaptic and extrasynaptic diazepam-insensitive GABA(A)Rs. CONCLUSIONS AND IMPLICATIONS The trans-retrochalcones are powerful positive allosteric modulators of synaptic and extrasynaptic GABA(A)Rs. These novel modulators act through an original mode, thus making them putative drug candidates in the treatment of GABA(A)-related disorders in vivo.
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